Submissions for variant NM_001042492.3(NF1):c.7513G>C (p.Ala2505Pro)

dbSNP: rs786202955

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166035	SCV000216796	uncertain significance	Hereditary cancer-predisposing syndrome	2014-10-08	criteria provided, single submitter	clinical testing	The p.A2505P variant (also known as c.7513G>C), located in coding exon 51 of the NF1 gene, results from a G to C substitution at nucleotide position 7513. The alanine at codon 2505 is replaced by proline, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 11,000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.A2505P remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001045536	SCV001209395	uncertain significance	Neurofibromatosis, type 1	2024-02-25	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2484 of the NF1 protein (p.Ala2484Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 186443). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NF1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV001045536	SCV002561098	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462198	SCV004198374	uncertain significance	Juvenile myelomonocytic leukemia	2023-08-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004558384	SCV005048519	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2017-08-17	criteria provided, single submitter	clinical testing	The c.7450G>C (p.A2484P) alteration is located in exon 50 (coding exon 50) of the NF1 gene. This alteration results from a G to C substitution at nucleotide position 7450, causing the alanine (A) at amino acid position 2484 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV005008081	SCV005639969	uncertain significance	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2024-04-08	criteria provided, single submitter	clinical testing